Xeroderma Pigmentosum B (XPB/ ERCC3/ p89) is an ATP-dependent 3' to 5' directed DNA helicase involved in basal RNA transcription and the nucleotide excision repair pathway (NER). While the role of NER in alleviating oxidative DNA damage has been acknowledged it remains poorly understood. By comparing fibroblasts from a patient suffering from Xeroderma Pigmentosum/ Cockayne Syndrome complex due to an XPB mutation with Normal fibroblasts, we found that deficiency in functional XPB paradoxically renders cells less sensitive to the cytotoxic effects of oxidative stress while increasing the genotoxic effects. XPB dysfunction also impedes damage response mechanisms. These effects are due to alterations in the cellular response to oxidative stress including important players such as p53 and telomeres. These findings have implications in the mechanisms of DNA repair, mutagenesis and carcinogenesis and aging in normal physiological systems. Our study expands knowledge of the role of XPB in protection against oxidative assault.